Single Nucleotide Polymorphisms at the TNFAIP3/A20 Locus and Susceptibility/Resistance to Inflammatory and Autoimmune Diseases

Mele, Alessandra; Cervantes, Jesus Revuelta; Chien, Victor; Friedman, David J.; Ferran, Christiane

doi:10.1007/978-1-4939-0398-6_10

Cited by 29 publications

(17 citation statements)

References 71 publications

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“…However, TNFAIP3 and TNIP1 mRNA expression was observed to be reduced in patients with SLE (38,39). Apparent discrepancies between the TNFAIP3 and TNIP1 mRNA expression reported in the current study, and those of earlier studies may be due to the dysfunction of TNFAIP3 and TNIP1 single nucleotide polymorphisms (SNP) in different regions (39,40). The National Center of Biotechnology Information (http://www.ncbi.nlm.nih.gov/) website database states that the SNP loci are in introns, exons, promoters, enhancers and other regions.…”

Section: Discussioncontrasting

confidence: 76%

C/EBP β mRNA expression is upregulated and positively correlated with the expression of TNIP1/TNFAIP3 in peripheral blood mononuclear cells from patients with systemic lupus erythematosus

Qian

Chen

Shi

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. CCAAT/enhancer-binding protein β (C/EBP β) has important roles in numerous signaling pathways. The expression of the majority of regulators and target gene products of C/EBP β, including tumor necrosis factor α-induced protein 3 (TNFAIP3) and TNFAIP3-interacting protein 1 (TNIP1), are upregulated in patients with systemic lupus erythematosus (SLE). The aim of the present study was to investigate whether C/EBP β expression is associated with SLE pathogenesis and correlates with TNIP1 and TNFAIP3 expression. Quantitative reverse transcription-polymerase chain reaction analysis was used to assess the expression of C/EBP β, TNIP1, and TNFAIP3 mRNA in peripheral blood mononuclear cells (PBMC) from 20 patients with SLE and 20 healthy controls. Spearman's rank test was used to determine the correlation between C/EBP β expression and SLE disease activity, and that between C/EBP β expression and TNIP1/TNFAIP3 expression in PBMCs from patients with SLE. C/EBP β mRNA expression was markedly increased in patients with SLE compared with healthy controls. The expression of C/EBP β was positively correlated with the SLE disease activity index and negatively correlated with the serum level of complement components C3 and C4. In addition, C/EBP β mRNA expression was increased in PBMCs from SLE patients that were positive for antinuclear, anti-Smith and anti-nRNP antibodies, compared with the antibody negative SLE patients. Furthermore, the mRNA expression levels of C/EBP β in patients with SLE was positively correlated with TNIP1 and TNFAIP3 expression.The results of the current study suggest that the increased expression of C/EBP β in PBMCs and the interaction between C/EBP β and TNIP1/TNFAIP3 may be involved in the pathogenesis of SLE. IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and is characterized by chronic inflammation with autoantibody production. The pathogenesis of SLE is complex and involves numerous immune cells and cytokines. B cells are known to have an essential role in autoantibody production in autoimmune disease (1). In addition, T cells have been recognized as a crucial component in the pathogenicity of SLE through their communication with B cells, which helps drive autoantibody production (2). In recent years, the importance of innate immunity in SLE pathogenesis has become increasingly evident, particularly regarding the role of Toll-like receptor (TLR) signaling pathways (3,4). Furthermore, the abnormal expression of certain cytokines and their receptors leads to immune hyperactivity in SLE; thus, cytokines such as interferon (IFN)-α, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) are considered to be therapeutic targets for SLE (5).Previous studies have determined that several cytokine genes are regulated by CCAAT/enhancer-binding protein β [C/EBP β, also known as nuclear factor for IL 6, cysteine rich protein 2, IL-6DBP, liver-enriched activating protein (LAP), NF-M, α1 acid glycoprotein/enhancer-binding protein, or ApC/EBP), which ...

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Section: Discussioncontrasting

confidence: 76%

C/EBP β mRNA expression is upregulated and positively correlated with the expression of TNIP1/TNFAIP3 in peripheral blood mononuclear cells from patients with systemic lupus erythematosus

Qian

Chen

Shi

et al. 2016

Experimental and Therapeutic Medicine

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“…The inflammatory symptoms seen in patients harboring ΔCT-NEMO forms are reminiscent of the inflammatory pathology seen in A20-deficient mice that experience arthritis, colitis, and dermatitis (34)(35)(36). TNFAIP3 SNPs that in some cases function to reduce A20 expression levels have been identified that confer susceptibility to rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and Behçets disease (37)(38)(39)(40). A recently described familial syndrome with reduced A20 function as a result of haploinsufficiency exhibits inflammatory disease phenotypes that are similar to those with ΔCT-NEMO mutation (41).…”

Section: Discussionmentioning

confidence: 99%

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

Zilberman‐Rudenko

Shawver

Wessel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-κB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-κB activation by NEMO, and its absence results in autoinflammatory disease.ctivation of the NF-κB family of transcription factors is required for normal development, innate and adaptive immunity, and the inflammatory response (1, 2). NF-κB-induced transcription of proinflammatory cytokines and chemokines amplifies immune-response programs and stimulates recruitment of inflammatory cells. Transcriptional activity of the classic NF-κB p65/p50 complex is regulated by the inhibitor of NF-κB kinase (IKK), consisting of the α-and β-catalytic subunits and the NEMO (NF-κB essential modulator, IKKγ) regulatory subunit. IKK activity leads to phosphorylation and K48-linked polyubiquitination of IκBα, the inhibitor of NF-κB. Ubiquitinated IκBα is then rapidly degraded, allowing nuclear translocation of NF-κB subunits and gene transactivation. NEMO functions as a scaffold within the IKK complex that is required for canonical IKK enzymatic activity and NF-κB activation (3).Activation of TNF, IL-1R, and Toll-like receptor (TLR) family receptors leads to K63 and linear (also termed M1) ubiquitination of cytosolic adapter proteins, such as receptor interacting protein 1 (RIP1). This in turn promotes recruitment of the IKK complex to the receptor signaling complex (4-8). A well-known negative regulator of NF-κB activation is A20 (encoded by the gene TNFAIP3). In the TNF-R1 complex, A20 removes K63-linked ubiquitin modifications on RIP1 through its deubiquitinase activity and converts these to K48-linked polyubiquitin chains through its E3 ligase activity (9). Editing of polyubiquitin linkages at the receptor complex in this manner results in rapid degradation of RIP1 and other signaling proteins, such as TRAF6, TRAF2, cIAP1, and cIAP2 (9, 10), promoting the termination of receptor-induced NF-κB activation. In addition, A20 directly inhibits IKK activity independently of its deubiquitinase activity in...

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“…However, we did not anticipate that ␥ T3 would augment A20 induction, an ubiquitin-editing enzyme ( 34 ). Single nucleotide polymorphisms in the Tnfaip3/A20 are associated with increased susceptibility to chronic infl ammatory diseases ( 35,36 ). Deletion of A20 has been shown to cause hypersensitivity to TNF-␣ due to the constitutive activation of NF B, leading to premature death ( 37 ).…”

Section: Inhibition Of A20 and Ampk Activation Altered Il-1 ␤ Secretimentioning

confidence: 97%

Suppression of NLRP3 inflammasome by γ-tocotrienol ameliorates type 2 diabetes

Kim

Wang

Okla

et al. 2016

Journal of Lipid Research

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Single Nucleotide Polymorphisms at the TNFAIP3/A20 Locus and Susceptibility/Resistance to Inflammatory and Autoimmune Diseases

Cited by 29 publications

References 71 publications

C/EBP β mRNA expression is upregulated and positively correlated with the expression of TNIP1/TNFAIP3 in peripheral blood mononuclear cells from patients with systemic lupus erythematosus

C/EBP β mRNA expression is upregulated and positively correlated with the expression of TNIP1/TNFAIP3 in peripheral blood mononuclear cells from patients with systemic lupus erythematosus

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

Suppression of NLRP3 inflammasome by γ-tocotrienol ameliorates type 2 diabetes

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